The Efficacy of Ketamine for Acute and Chronic Pain in Patients with Cancer: A Systematic Review of Randomized Controlled Trials

Managing cancer-related pain poses significant challenges, prompting research into alternative approaches such as ketamine. This systematic review aims to analyze and summarize the impact of ketamine as an adjuvant to opioid therapy for cancer-related pain. We conducted a literature review in MEDLINE, EMBASE, and Scopus from 1 January 1982 to 20 October 2023. Abstracts were screened against inclusion criteria, and eligible studies underwent a full-text review. Data was extracted from the included studies, and a framework analysis approach summarized the evidence regarding ketamine’s use in patients with cancer. A total of 21 randomized clinical trials were included, and the quality of all the included studies was good or fair. Significant improvements in pain scores and reduced morphine consumption were consistently observed with intravenous ketamine administration for postoperative pain control, particularly when combined with other analgesics such as morphine. Ketamine was less effective when used as an analgesic for chronic pain management, with several studies on neuropathic pain or chemotherapy-induced neuropathy finding minimal significant effect on reduction of pain scores or morphine requirements. The efficacy of ketamine in pain management appears to depend on factors such as dosage, route of administration, and patient population.


Introduction
Despite advancements in pharmacological therapies and understanding of the molecular mechanisms underlying cancer pain, the prevalence of cancer pain remains high [1].Systematic reviews and meta-analyses reveal that over one-third of patients experience pain related to cancer after curative treatment, and two-thirds of patients with advanced or metastatic cancer report symptoms of pain [1,2].Studies showed up to 20% of patients with cancer undergoing opioid titration develop refractory pain or experience a poor analgesic response and intolerable side effects [3,4].Patients with cancer may also undergo a variety of surgeries, with pain being an expected outcome.Pain may develop because of the tumor itself, either through the obstruction of surrounding structures or invasion of tissue and subsequent inflammation [5].Pre-existing oncological pain and opioid tolerance represent unique challenges in managing acute pain in the perioperative period in this specific population [6].Additionally, chemotherapy-induced peripheral neuropathy (CIPN) is a common and challenging side effect associated with many anticancer agents that persists in 30% of patients following chemotherapy [7].Inadequate pain management in cancer patients adversely affects physical function, compromises psychological well-being, disrupts social interactions, leads to increased emergency department visits and hospitalization, and undermines the effectiveness of antitumor treatment [8,9].
The management of moderate to severe cancer-related pain involves a combination of opioid analgesics administered in rotation and through dose titration to mitigate the effects of opioid toxicity [3,[10][11][12].The advent of stepwise multimodal approaches to pain management necessitates alternative therapeutic strategies beyond opioid administration to alleviate the symptoms associated with cancer-related pain.Ketamine, typically used as an anesthetic, is a N-methyl-D-aspartate (NMDA) antagonist capable of treating acute and chronic pain at low, subanesthetic doses [13].Despite growing evidence regarding the benefits of ketamine as a rapid antidepressant and antisuicidal agent, [14] its efficacy in the treatment of chronic cancer pain remains unclear [15,16].Ketamine can be administered as an adjuvant to opioid therapy in patients with cancer when their pain becomes opioidresistant, improving patient outcomes and quality of life [4,17].The various modes by which ketamine can be administered, along with variability in dosage and duration, pose a challenge in the creation of standardized treatment guidelines for this drug.Many clinicians may hesitate to administer ketamine considering the ambiguous clinical evidence and adverse event profile associated with the treatment [17].
This review aims to systematically summarize and analyze the existing literature on ketamine administration within the cancer population.The review specifically focuses on the effectiveness of ketamine as an adjuvant to opioid therapy for managing both acute and chronic pain among patients with cancer.Additionally, the review compares and reports different methods of ketamine administration in conjunction with opioids to identify optimal approaches for maximizing efficacy and minimizing side effects.

Materials and Methods
A systematic literature review was conducted according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines (Appendix A).The study protocol was registered in the International Prospective Register of Systematic Reviews (PROSPERO) (registration number: CRD42022347551).

Study Inclusion and Exclusion Criteria
The inclusion criteria of the review consisted of articles assessing the relationship between administering ketamine to adult patients with cancer and pain.Additionally, articles were required to be peer-reviewed, report the results of a randomized controlled trial (RCT), and written in the English language.We decided to only include RCTs because systematic reviews of RCTs are regarded as the highest quality evidence [18,19].Articles were excluded if the target population was children (younger than 18), in addition to any articles focused only on molecular aspects of ketamine.A detailed list of inclusion and exclusion criteria can be found in Appendix B.

Information Sources and Search Strategy
The initial search was intentionally broad to capture the inclusion criteria and to minimize the risk of overlooking potentially relevant studies.Cancer and ketamine administration were the main components of the search strategy.Using a combination of subject headings and keywords, the search strategy was implemented into MEDLINE ® (via PubMed ® , Bethesda, MD, USA), EMBASE, and Scopus from 1 January 1982 to 20 October 2023, when all searches were completed.The citations of included studies for relevant articles and references were manually scanned from similar systematic reviews to ensure no relevant studies were missed during indexing.Gray literature was not included, as we considered only peer-reviewed published studies.To exclude animal studies, we applied the Cochrane human studies filter.We also added a systematic review keyword and publication type filter to exclude systematic review articles.Appendix C shows the complete strategy for each of the searches.

Study Selection Process
Two researchers screened the titles and abstracts against the eligibility criteria.Discrepancies were resolved through discussions between members of each pair.When necessary, a third team member reviewed the discrepancy until a consensus was reached.Inter-rater reliability of reviews was achieved by ensuring three iterations of sample reviews were conducted with each person reviewing 30 articles until an average agreement of 83% was reached.The full-text articles were screened in a similar manner.

Study Quality Assessment
Two independent researchers assessed the quality of included studies using the NIH Quality Assessment Tool for the controlled intervention studies [20].We assigned the quality of each study as good, fair, or poor (see Appendix D), and any disagreements in the risk of bias scoring were resolved by consensus or by a discussion with a third author.

Data Extraction and Analysis
A meta-analysis was not conducted due to heterogeneity in populations and in how pain was measured.Using a framework analysis approach, we summarized the evidence on using ketamine in patients with cancer [21].The framework analysis approach consisted of five stages: familiarization, framework selection, indexing, charting, and mapping and interpretation.
First, team members familiarized themselves with the literature in addition to reading included studies.Second, conceptual frameworks were identified that served as the codes for data abstraction.We used a thematic framework to describe studies in which research has investigated administering ketamine in patients with cancer, which included: publication year, design, outcome(s), type of cancer, objective(s), country, setting, dosage, outcomes, and the relationship between using the ketamine and outcomes.Data were also collected on the route of ketamine administration (e.g., infusion and intranasal).Pairs of authors completed charting and indexing by inputting selected text from included studies into the appropriate cells within our framework.Data extraction from the included studies was achieved using a standardized data extraction form in Microsoft Excel (version 2016).Last, extracted data were analyzed from each cell to describe the studies and findings of using ketamine in patients with cancer.

Study Selection
The searches in PubMed, Embase, and Scopus yielded 1487 citations.These citations were exported to Endnote (Version 20), and 33 duplicates were removed using the Endnote deduplication feature.This resulted in a total of 1454 unique citations found across all database searches.As can be seen in Figure 1, titles and abstracts of the 1454 articles were screened; 306 were selected for full-text screening.Of the 306 studies, 285 were excluded at full-text screening or during extraction attempts with the consensus of two co-authors; 21 unique eligible studies were included .
were screened; 306 were selected for full-text screening.Of the 306 studies, 285 were excluded at full-text screening or during extraction attempts with the consensus of two coauthors; 21 unique eligible studies were included .

Characteristics of Included Studies
The included studies were published between 2001 and 2019.Included studies focused on different cancer types, including but not limited to abdominal cancer, breast cancer, lung cancer, colon cancer, and prostate cancer.Characteristics of included studies are shown in Table 1.We found that outcomes were primarily divided into two categories: treatment of pain postoperatively in patients with cancer undergoing oncologic surgery or treatment for refractory pain.Several studies also examined CIPN as a component of cancer-related pain.Ketamine was administered via various modes of delivery, including intrathecally, intramuscularly, subcutaneously, topically, orally, and intravenously.

Size Mean Age Country Setting
A. Abd El-Rahman et al. [23] Compare the postoperative analgesic effect of local ketamine 1 mg/kg instilled in the wound to that of intramuscular ketamine and of placebo after total thyroidectomy.

Quality Assessment of Included Studies
The quality of all the included studies was good or fair.The details of the quality assessment of the included studies are shown in Appendix D.

Intravenous Administration of Ketamine
Eight studies examined the effect of intravenously administered ketamine on pain scores in patients with cancer [25,26,32,33,36,37,39,42]. While all eight studies examined pain as either a primary or secondary outcome, the type of pain assessed varied.Six studies investigated the effect of peri-or pre-operative ketamine on reducing postoperative pain scores following oncologic surgery in the inpatient setting [25,26,33,36,37,39], including pain at surgical sites [32], and one study focused on the use of ketamine for chronic pain therapy [42].Further characteristics of the studies, such as the dosage and types of pain scores utilized, can be found in Table 2. Most studies examining postoperative outcomes used the visual analog scale (VAS) to evaluate pain scores [26,33,36,37,39,42].Ketamine was used as the sole pharmacological treatment in only two of the eight studies [26,32].Other studies compared the efficacy of morphine in combination with ketamine in reducing pain scores [25,33].The median morphine equivalent daily dose for both arms was 0 mg.
No, ketamine was equivalent to a placebo for cancer-related neuropathic pain.
Ishizuka et al. [30] 10 mg of ketamine Pain severity was evaluated through a verbal scale, in which patients used the following scores: no pain = 0, mild = 1, moderate = 2, and severe = 3.
Measured for four weeks, with interviews on the 7th, 14th, 21st, and 28th days Oral morphine, 10 mg every 6 h, adjusted to every four hours if needed.The dose of morphine was increased (5 mg) whenever necessary, in each weekly evaluation, during the study.
No, a reduction in the need for opioids, lower pain scores, or greater pain relief in patients taking S(+) ketamine was not observed when compared to the placebo group, which goes against the reports in the literature for racemic ketamine.No, it had a strong placebo effect and failed to show any additional clinical benefit for ketamine when delivered subcutaneously in a dose-escalating regimen over 5 days, while significantly increasing toxicity.

Effect on Pain Scores
Seven of the eight studies found significant improvement in pain scores following administration of ketamine [25,26,32,33,36,39,42].However, while one study concluded that intraoperative infusions of ketamine helped postoperative pain up to three months after breast cancer surgery, it failed to reduce clinically significant pain and improve patients' quality of life [32].One of the eight studies did not find significant improvement in pain scores following administration of ketamine.The study found that IV ketamine administered throughout surgery reduced postoperative consumption of morphine but that there was no significant difference in VAS scores following surgery [37].

Intrathecal Administration of Ketamine
Three of the included studies examined outcomes of pain associated with intrathecal administration of ketamine hydrochloride [22,34,38].Two of the studies specifically looked at postoperative pain following oncological surgeries and procedures with a one-time dose of 0.1 mg/kg ketamine administered perioperatively [22,38] and one study [34] examined the use of 0.2 mg/kg ketamine for visual analog scores > 3/10 over a 25 day period in refractory cancer pain therapy in combination with morphine to evaluate analgesic effects.

Effect on Pain Scores
Significant improvement in pain scores was found with administration of morphine in conjunction with intrathecal ketamine.One study found that a combination of bupivacaine, dexmedetomidine, and ketamine significantly improved postoperative analgesia when compared to either drug (dexmedetomidine or ketamine) alone [38].In a similar surgical setting, a combination of intrathecal ketamine with morphine reduced total postoperative morphine consumption with good overall postoperative analgesia when compared to either drug alone [22].Another study concluded that ketamine enhanced epidural morphine analgesia when administered in the early stages of terminal cancer pain therapy without increasing the incidence of adverse effects, while also reducing morphine requirement during the period of observation [34].

Intramuscular Administration of Ketamine
Four studies examined intramuscular administration of ketamine for the treatment of postoperative pain [23,31,40,41].As seen in Table 2, one study examined a constant, fixed dose of ketamine [23], while the other compared escalating doses of intramuscular ketamine [41].Preoperatively, a third study used 1 mg/kg ketamine in a Pecs block prior to breast cancer surgery [40].Similarly, another study used either 0.5 mg/kg or 1 mg/kg of ketamine as part of a total peripheral nerve block in conjunction with bupivacaine [31].

Effect on Pain Scores
Two studies found that ketamine administration resulted in lower acute pain scores and morphine consumption following surgery [23,41].Preoperatively, a modified Pecs block (ketamine + bupivacaine) prolonged the time to first request of analgesia and reduced total opioid consumption [40].Ketamine, in addition to bupivacaine, as a peripheral nerve block preoperatively was also associated with lower morphine PCA consumption and longer analgesic effects [31].

Subcutaneous Infusion of Ketamine
One study examined the effects of subcutaneous infusions of ketamine as pain therapy for refractory cancer pain [29].Ketamine alone was compared to placebo.As seen in Table 2, pain was evaluated with the Brief Pain Inventory score.The study utilized a dose-escalating regimen (100, 300, or 500 mg) of ketamine over a 5-day period in the treatment of refractory cancer pain.

Effect on Pain Scores
This study examining the effect of subcutaneous ketamine infusion on chronic cancer pain found that ketamine did not have a net clinical benefit when used as an adjunct to opioids and standard analgesics in refractory cancer pain [29].

Topical Administration of Ketamine
Two studies examined the topical administration of ketamine for the purpose of alleviating CIPN [24,28].Similar dosages of ketamine (in addition to amitriptyline) were used in one study using up to 80mg of ketamine cream [28] compared to 20mg of ketamine applied twice daily in the other study [24].

Effect on Pain Scores
The study that utilized a greater dosage of ketamine suggested that two percent ketamine plus 4% amitriptyline cream does not decrease CIPN symptoms in cancer survivors [28].Similarly, while pain scores improved following the administration of ketamine cream in the other study, the overall effect size was not large [24].

Oral Administration of Ketamine
Three studies assessed pain outcomes following oral administration of ketamine [27,30,35].All studies examined either refractory oncogenic pain [35] or neuropathic pain [27,30].Varied dosages of ketamine were used, as seen in Table 2.

Effect on Pain Scores
Pain scales varied, with one study using the VAS [35], and another using an index pain score from the sensory component of the short form McGill Pain Questionnaire [27].While the studies examining neuropathic pain found no significant improvement in pain scores when compared to placebo [27,30], the study investigating refractory oncogenic pain found that ketamine was an effective co-adjuvant analgesic with morphine compared to morphine alone [35].One study examining neuropathic pain noted the small number of patients studied, with only 22 patients analyzed following 6 drop-outs [30].

Adverse Effects of Ketamine
All studies assessed adverse side effects occurring following administration of ketamine, including psychiatric side effects or other adverse effects related to changes in blood pressure and respiratory, cardiovascular, or gastrointestinal changes.As can be seen in Table 3, side effects were assessed with a variety of different scales, including the Profile of Mood States (POMS) or through clinical signs such as heart rate.Most of the included studies reported minimal to no psychiatric side effects (such as dissociation, psychosis, or changes to cognition) with the administration of ketamine.One study found significant intergroup differences in the development of psychotoxicity following ketamine administration [29].Other adverse effects included rash, constipation, dry mouth, confusion, and a depressed level of consciousness.No significant differences in toxicities were observed between the BAK arm and the placebo throughout the 4 weeks of the study.
No psychiatric side effects were assessed.
Other adverse effects included: on the day of surgery, adverse effect bladder spasms were reported in 46.4% (n = 13) of patients in the MMA group compared with 40.7% (n = 13) of patients in the PCA group, and PONV was reported in 17.9% (n = 5) of patients in the MMA group compared with 18.5% (n = 5) of patients in the PCA group.On postoperative days one and two, the episodes of PONV and bladder spasms were greatly reduced; fewer of these episodes and less constipation in the MMA group than in the PCA group, although none of the differences were statistically significant.This inquiry was performed by phone and confirmed by mail.The incidence and importance of postoperative residual pain were evaluated at 2 weeks, 1 month, 6 months, and 1 year after surgery.

None of the considered patients
experienced nightmares or psychotomimetic effects, whereas one patient in group 5 presented with hallucinations on the fourth postoperative day.No intergroup differences were noted in the results of the psychometric evaluations.
For other adverse effects, the incidence of postoperative nausea was low in all the groups considered.Approximately 90% of patients presented with less than five episodes of nausea or vomiting during the 72 first postoperative hours.

Fallon et al. [27]
Mean and worst pain; mood Hospital Anxiety and Depression Score, a self-administered anxiety and depression screening tool for use in nonpsychiatric patients.The tool has 14 items, which focus on the emotional and cognitive aspects of each aspect.Each item is scored from 0 to 3 for a combined maximum of 21 for each aspect, with higher scores reflecting a higher symptom load; mean change in global distress in the last 24 h There were 18 serious adverse events: 8 in patients receiving ketamine and 10 in patients receiving placebo.Common adverse events were cognitive disturbance, dizziness, fatigue, nausea, and somnolence.

Gewandter et al. [28] N/a N/a
No psychiatric side effects were assessed.
Adverse events (AEs) were assessed in the intent to treat population (n = 458).Two hundred ninety-five AEs were reported during the study; 147 occurred in the KA (ketamine) group and 158 occurred in the placebo group.Eight serious AEs were reported, with four in each arm.Twenty-one AEs were severe; ten occurred in the KA group and 11 in the placebo group.Five of the severe AEs were classified as musculoskeletal, two as swelling, and one as fatigue.The percent of subjects reporting AEs of all classes was similar between arms, although the study was not powered to detect differences in AEs.Compared with the odds of the placebo group, the odds of the ketamine group experiencing psychotoxicity increased each day, becoming significant after day 3.For those with toxicity, when the level of toxicity between arms was compared, the ketamine group was more likely to report higher scores each day.By study end, the difference between groups was significant.
There were relatively few adverse events higher than grade 3 in severity and worse than baseline (14 for ketamine; 16 for placebo).The most common were light-headedness (five cases), hypoxia (five cases), and somnolence (nine cases).Seven serious adverse events were reported, two of which (bradyarrhythmia and cardiac arrest, both in patients receiving ketamine) were thought to be possibly related to the study drug.
Ishizuka et al. [30] N/a N/a The side effects observed did not show statistically significant differences between the groups, and constipation was reported by more than 60% of the patients in both groups.Nausea was present in 55% of the patients in G1 (morphine + ketamine) and in 30% of the patients in G2 (morphine alone), and vomiting was reported by 44% of the patients in G1 and in 23% of the patients in G2.Only three patients who took S(+) ketamine complained of sleepiness and delirium, but it did not prevent them from completing the study protocol.

Measured by Douleur Neuropathique 4 (DN4) questions, assessed every month for the first three consecutive postoperative months
No psychiatric side effects were assessed.
Perioperative adverse events were treated and recorded, such as nausea, vomiting, hypotension, hypertension, bradycardia, tachycardia, nystagmus, dizziness, emergence phenomenon, and sedation.There were no significant differences between the studied groups in the incidence of postoperative adverse effects or surgical complications.No psychiatric side effects were assessed.
The MO (morphine group) patients' rate of nausea and vomiting (PONV) was higher than that of the MK patients (morphine + ketamine group) (p < 0.05); all incidents were short-lived and responded well to metoclopramide.No ketamine-specific side effects were recorded; no patient of either group returned to the operating room for resurgery.
Lauretti, Gomes et al. [34] Adverse effects assessment Total number of patients complaining per total per group There were no differences in adverse side effects among the groups.The only patient who suffered from hallucinations in the KG complained 28 days after the introduction of the study drug.
Other adverse effects included somnolence, constipation, diminished appetite, skin redness/pain to epidural administration, back pain, nausea, or vomiting (no statistically significant differences among groups).
Lauretti, Lima et al. [35] The daily consumption of morphine Measured throughout the course of the study (30 days) on days 1, 5, 10, 15, 20, and 30 after the test drug was introduced One patient from the KG (ketamine group) reported frequent hallucinations, and the oral dose was changed from 0.5 mg/kg to 0.25 mg/kg twice daily.
One patient from the NG (nitroglycerin group) was withdrawn from the study because of an intense headache and was replaced by another patient to keep 15 patients in each group.Patients from the CG (control group) and the DG (dipyrone group) reported more somnolence compared with the KG and the NG (p < 0.013).This inquiry was performed by the research nurse with a phone call and was confirmed by mail.
None of the considered patients experienced nightmares or psychomimetic effects.
The incidence of postoperative nausea was low in all the groups considered.Orthostatic hypotension at first mobilization was significantly lower in patients receiving intravenous analgesia than in patients benefiting from epidural analgesia

Mahran et al. [37] Sedation
Measured by a 4-point scale.(0-awake and alert, 1-mildly sedated, 2-moderately sedated, aroused by shaking, 3-deeply sedated, difficult to arouse even by shaking) in the first postoperative 24 h Complications such as dizziness, visual disturbance, nightmares, and hallucinations were not recorded by any of the patients included in this study during the first 24 h of the postoperative period.No other adverse effects were assessed.

Mohamed et al. [38]
Postoperative adverse events N/a Nausea, vomiting, hypotension, bradycardia, cardiac arrhythmias, nystagmus, dissociative effects, strange feelings, dizziness, chest pain, dreams, and sedation.There was no significant difference among groups regarding postoperative sedation score except immediately postoperative, where there was a significant increase in sedation score in groups II (ketamine group) and III (dexmedetomidine + ketamine group) compared to group I (dexmedetomidine) (p = 0.02).There was a significant difference in the incidence of sedation (p < 0.03) in groups II and III compared to group I.
Groups II and III had a higher incidence of sedation (3 [10.0%] and 5 [16.7%], respectively) compared to group I (0 [0.00%]).Apart from sedation, there were no significant differences in the incidence of other side effects between the 3 studied groups.Other adverse effects included dizziness and nausea.

Shah et al. [42]
Incidence of postoperative constipation, pruritus, PONV, HR, and MAP and time to discharge from SICU Measured by clinical exam and patient interview at induction, intubation, surgical incision, every 15 min thereafter, end surgery, and one, two, four, eight, and 24 h postoperatively No psychiatric side effects were assessed.
The most common adverse effects observed in the studies included nausea and vomiting [22,23,25,26,28,30,31,33,34,36,[38][39][40]42].In these studies, there were no significant differences between placebo and treatment groups in the incidence of gastrointestinal side effects such as nausea and vomiting.One study reported bladder spasms in 46.4% of patients in the treatment group; however, this effect was greatly reduced on postoperative days 1 and 2, with no differences being statistically significant [25].Serious adverse effects, such as bradyarrhythmia [29,31,38] and cardiac arrest [29], were reported in some studies.Immediate postoperative sedation score was significantly increased in groups of patients administered ketamine compared to the control group in one study [38].

Discussion
To our knowledge, this is the first review focusing specifically on RCTs regarding the effectiveness of various forms of ketamine as an adjuvant to opioid therapy for managing acute and chronic pain among patients with cancer.Our results showed ketamine was most effective when used in conjunction with another analgesic such as morphine.When ketamine was used to reduce postoperative pain levels and morphine requirements postoperatively, it showed significant improvements in 13 of 14 studies [22,23,25,26,[31][32][33]36,[38][39][40][41][42].However, ketamine was less effective when used as an analgesic for other types of pain arising from cancer, with four of the seven stud-ies examining refractory cancer pain or neuropathic pain finding minimal effect on the reduction of pain scores or morphine requirements [27][28][29][30].While multiple studies have shown that ketamine reduces refractory cancer pain [43][44][45], its use as a viable treatment option remains controversial.The difficulty in assessing effective pain control may lie in the heterogeneity of the cancer population and difficulty in defining outcomes in relation to pain.Psychological factors may also contribute to increased pain amongst patients with cancer, which might necessitate a more comprehensive approach than just the application of one intervention.
Our results showed that intravenous ketamine was most commonly used to reduce postoperative pain scores in the setting of acute pain rather than for refractory cancer pain.Ketamine was most often used preoperatively or intraoperatively via intravenous administration for postoperative pain control.Of the eight studies that examined postoperative pain control with intravenous ketamine, seven found that subanesthetic doses of ketamine significantly reduced pain outcomes or morphine consumption following surgery.Four of those studies used ketamine in conjunction with another analgesic agent such as morphine [25,33,39,42].The use of ketamine as an opiate-sparing agent may be particularly important for patients who may have a tolerance to opiates.Patients with cancer and chronic cancer-related pain are more likely to have developed tolerance to opiates as a form of pain control [46].Currently, the indications for esketamine, the "S" enantiomer form of ketamine, do not extend beyond treatment-resistant depression and suicidality [47].Independent of long-term opioid therapy, depression is prevalent in 20-30% of patients with cancer [48].Studies show that a bidirectional relationship may exist between depression and long-term opioid therapy in the treatment of non-cancer related pain [49][50][51][52].While fewer studies have examined this relationship within the population of patients with cancer, the possible interdependence of depression and opioid use suggests a potential role for ketamine in addressing the difficulties of treating chronic cancer pain that may be refractory to opiate medications or neuropathic in nature.When considering the potential role of ketamine in chronic cancer pain management, the available data suggests that ketamine may be more efficacious when used in conjunction with an adjuvant analgesic.As a result, the introduction of novel analgesic agents such as ketamine may be integral in multimodal pain regimens for patients with cancer to address comorbidities such as depression and reduce requirements for opioid medications.
When used in combination with agents such as morphine as part of multimodal pain control, multiple studies demonstrated that ketamine is more likely to reduce pain scores and postoperative morphine consumption.This may be due to the fact that ketamine can attenuate morphine tolerance by increasing concentrations of morphine within the brain [53].Ultimately, further research is needed to determine the degree to which the addition of ketamine to chronic cancer pain management may improve pain outcomes, along with consumption of oral morphine equivalents, throughout a patient's experience with their disease.
This review showed that intrathecal administration of ketamine was most effective in reducing postoperative pain and terminal cancer pain in conjunction with other agents.The primary adjuvant agent administered with ketamine was morphine.Other agents utilized in conjunction with ketamine included bupivacaine and dexmedetomidine.These results are in line with previous research on intrathecal utilization of ketamine.In one metaanalysis of intrathecal administration of ketamine as an adjunct to bupivacaine following a variety of surgical procedures (including lower abdominal and lower limb surgery), time to first analgesic request was prolonged [54].More studies are needed to determine the duration of the effects of ketamine following intrathecal administration.The benefits of intrathecal administration may be more prominent for postoperative pain outcomes rather than as an adjunct in treatment modalities for terminal cancer pain.
Administration of ketamine alone was most commonly performed in studies examining the intramuscular approach.Ketamine administration both before and after surgery was found to significantly reduce postoperative pain scores and delay rescue analgesia with morphine.
Included studies only examined oral administration in relation to pain outcomes associated with chronic cancer pain therapy.The highest dosage of ketamine of all 21 studies was utilized during oral administration, with up to 400 mg/day administered for patients [27].However, this study did not find ketamine to have significantly greater effects than placebo, suggesting that escalating doses of oral ketamine are not effective for chronic cancer pain therapy.In addition, the efficacy of ketamine in this study was analyzed with respect to CIPN, which was the least investigated type of pain across all included studies.The lack of consistency in the assessment and diagnosis of CIPN may also make it difficult to assess for clinical improvements [7].
Finally, ketamine's side effects, mainly neurological side effects, pose challenges to its utilization, emphasizing the importance of exploring alternative modes.Topical analgesics may play an important role in chronic pain management without the serious side effects associated with the medication.However, the two included studies [24,28] that evaluated topical ketamine use found that there was limited effect for CIPN.Of note, the daily dosages used for topical administration ranged from 40 mg to 80 mg.As no adverse systemic effects were reported at those doses in either study, further research on increased titration of ketamine within analgesic creams is warranted.
This review has several limitations.First, cancer-related pain may manifest differently, depending on the location of the tumor as well as the nature and severity of the cancer.In this aspect, the efficacy of ketamine in addressing pain may not be generalizable to all types and degrees of cancer.In addition, the analysis of pain, an already subjective measure, was investigated using a variety of scales across included studies.This could potentially influence the interpretation of the clinical efficacy of ketamine within our review.Second, in our assessment of the efficacy of ketamine for treatment of pain in cancer patients, we excluded studies that focused only on biological aspects of ketamine and thus may have missed papers that provided explanations of the molecular pathway between ketamine and pain.Finally, we may have missed relevant papers published in other languages by limiting our systematic review to English-only articles.

Conclusions
Intravenous ketamine, in dosages ranging from 0.1 mg/kg to 0.5 mg/kg, was most efficacious in improving pain scores in patients with cancer for up to 72 h following surgery, particularly in conjunction with other analgesics such as morphine.Fewer studies examined the use of ketamine for pain therapy, and those that did found less benefit in terms of pain scores following treatment for refractory chronic cancer pain (including CIPN).Ketamine was well tolerated across all studies that examined the side effects associated with ketamine administration.

Eligibility criteria 5
Specify the inclusion and exclusion criteria for the review and how studies were grouped for the syntheses.
Page 5 Information 6 Specify all databases, registers, websites, organizations, reference lists, and other sources searched or consulted to identify studies.Specify the date when each source was last searched or consulted.
Pages 5 and 6

Search strategy 7
Present the full search strategies for all databases, registers, and websites, including any filters and limits used.

Pages 5 and 6
Selection process 8 Specify the methods used to decide whether a study met the inclusion criteria of the review, including how many reviewers screened each record and each report retrieved, whether they worked independently, and, if applicable, details of automation tools used in the process.Page 6 Data collection process 9 Specify the methods used to collect data from reports, including how many reviewers collected data from each report, whether they worked independently, any processes for obtaining or confirming data from study investigators, and if applicable, details of automation tools used in the process.
Pages 6 and 7

Data items 10a
List and define all outcomes for which data were sought.Specify whether all results that were compatible with each outcome domain in each study were sought (e.g., for all measures, time points, and analyses), and if not, the methods used to decide which results to collect.

Pages 6 and 7 10b
List and define all other variables for which data were sought (e.g., participant and intervention characteristics, and funding sources).Describe any assumptions made about any missing or unclear information.
Pages 6 and 7

Study risk of bias assessment 11
Specify the methods used to assess the risk of bias in the included studies, including details of the tool(s) used, how many reviewers assessed each study and whether they worked independently, and if applicable, details of automation tools used in the process.
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Effect measures 12
Specify for each outcome the effect measure(s) (e.g., risk ratio and mean difference) used in the synthesis or presentation of results.

Synthesis methods 13a
Describe the processes used to decide which studies were eligible for each synthesis (e.g., tabulating the study intervention characteristics and comparing them against the planned groups for each synthesis (item #5)).Describe any methods used to synthesize results and provide a rationale for the choice(s).If meta-analysis was performed, describe the model(s), method(s) to identify the presence and extent of statistical heterogeneity, and software package(s) used.

NA 13e
Describe any methods used to explore possible causes of heterogeneity among study results (e.g., subgroup analysis and meta-regression).

NA 13f
Describe any sensitivity analyses conducted to assess the robustness of the synthesized results.NA

Reporting bias assessments 14
Describe any methods used to assess the risk of bias due to missing results in a synthesis (arising from reporting biases).

NA Certainty assessment 15
Describe any methods used to assess certainty (or confidence) in the body of evidence for an outcome.NA

Study selection 16a
Describe the results of the search and selection process, from the number of records identified in the search to the number of studies included in the review, ideally using a flow diagram.
statement of the objective(s) or question(s) the review addresses.Page 5

Pages 6 and 7 13bPages 6 and 7 13c
Describe any methods required to prepare the data for presentation or synthesis, such as handling missing summary statistics or data conversions.Describe any methods used to tabulate or visually display the results of individual studies and syntheses.

Table 1 .
Characteristics of the included studies.

Table 2 .
Ketamine administration details and its effectiveness on pain management based on route of administration.

Table 3 .
Secondary outcomes and side effects reported in included studies.

Quality Assessment Tools Used for Assessing the Quality of Included Studies NIH
Quality Assessment Tool and Ratings for the Controlled Intervention Studies